One out of every fifty people living in the United States suffers from some form of paralysis, a total of almost 6 million Americans. This proposal outlines the translational development of a cellular therapeutic already in clinical trials with a novel, regenerative peptide to be used in combination for treatment of spinal cord injury (SCI) and associated dysfunction. Preclinical data from Athersys has demonstrated that acute intravenous administration of bone marrow-derived multipotent adult progenitor cells (MAPC) provides immediate and durable neuroprotection after SCI. Benefit to locomotor recovery was seen beginning at one week post injury, as well as significant sparing of white matter tracts. Dr. Silver and his colleagues have identified the glial scar as a significant impediment to long distance regeneration, specifically inhibitory molecules known as chondroitin sulfate proteoglycans (CSPGs). After discovering the receptor and signaling pathways associated with this pathway, Dr. Silver's laboratory has developed a novel peptide, Intracellular Sigma Peptide (ISP), which modulates the key receptor in this pathway. In a preclinical study, long term subcutaneous treatment with this peptide initiated in the acute phase following spinal cord injury allowed for delayed recovery of locomotion and bladder behaviors following SCI. Interestingly, while ISP treatment resulted in recovery it had no neuroprotective effects. In the 6 month time frame of this Phase I project, we propose to combine the use of MAPC with ISP treatment following a translationally relevant rodent model of contusive SCI with the therapeutic aims of i) promoting enhanced neuroprotection, and ii) enhancing sprouting/regeneration by altering the response of regenerating axons to inhibitory extracellular matrix. We will evaluate the synergistic effects of treatment by analyzing improvements in motor hind limb recovery, return of coordinated control of the lower urinary tract and quantification of neuronal sprouting/regeneration. Dr. Silver and collaborators have been investigating the ability of ISP peptide to induce sympathetic neural regeneration and alleviate arrhythmia following myocardial ischemia/reperfusion injury. This data suggests that ISP could also be utilized in other disorders in which CSPGs play a critical inhibitory role, such as traumatic brain injury, multiple sclerosis and stroke. The fact that MAPC has already proven efficacious in preclinical models of acute myocardial infarction, multiple sclerosis, traumatic brain injury and stroke dramatically expands the impact that this combinatorial therapy could have in the field of regenerative medicine. If MAPC and ISP administration can be shown to be effective in ameliorating SCI associated deficits and dysfunction, this therapy could relieve some of the economic burden on the direct and indirect costs associated with SCI related care, and more importantly provide meaningful improvement to SCI patients. Both treatments are non- invasive and systemic, making them highly attractive therapeutic options for clinical use.